Components of the MetS constellation -- such as central obesity, atherogenic dyslipidemia, endothelial dysfunction, impaired fasting glucose/insulin resistance, and hypertension -- have been implicated in life-threatening cardiovascular diseases. But as for OA, after adjusting for body mass index (BMI), David T. Felson, MD, MPH, section chief of the Clinical Epidemiology Research & Training Unit of Boston University School of Medicine, and colleagues, found no significant connection. "There may be an association with high blood pressure that needs further study, however," they wrote.

Recent research has attempted to identify the relationship of particular MetS components with different diseases in order to shed light on the influence of MetS on disease pathogenesis. In the musculoskeletal context, central obesity is related to higher body mass index (BMI), an established risk factor for knee OA, and other elements in the MetS constellation are thought to promote OA through low-grade inflammation, which may alter the microvasculature of subchondral bone or cause neuromuscular impairment.

In 1992-1995, a total of 1,083 participants from the Framingham Offspring Cohort (descendants of the original Framingham Heart Study cohort and their spouses) were assessed in the OA study. Participants were evaluated near baseline for MetS components, and those with existing OA were excluded. The final 991 participants had a mean age of 54.2, and 55.1% were women. MetS was present in 26.7% of the men and 22.9% of the women. More participants without MetS were college-educated.

The cohort was followed up for OA in 2002-2005. Felson and colleagues defined radiographic OA as a knee without baseline disease that developed Kellgren and Lawrence grade >2 at follow-up. Incident symptomatic OA was deemed present when a knee developed pain and stiffness in the presence of radiographic RA.

While MetS components were initially associated with both incident radiographic and symptomatic OA, after adjustment for BMI, almost all the associations became weak and insignificant. Nevertheless, an association between high blood pressure, especially diastolic, and OA outcomes persisted in both sexes.

OA was relatively infrequent, the results showed. In knees with no baseline radiographic OA, the incidence was 9.8% (78 of 800 knees) in men and 10.5% (105 of 1,003 knees) in women. After adjusting for age, education, smoking status, alcohol consumption, and physical activity, the researchers found that MetS-related abdominal obesity and low high-density lipoprotein cholesterol were associated with an increased OA incidence among men. Among women, abdominal obesity and high blood pressure were associated with incident radiographic OA, while MetS was not. After adjustment for BMI or body weight, however, none of these associations remained significant.

Surprisingly, Felson and his associates found a post-adjustment inverse association of fasting blood sugar with OA, especially symptomatic OA, whereas previous research has reported that diabetes and elevated blood glucose were reported to be positively associated with OA and joint replacement.

An accompanying editorial by Tom Appleton, MD, PhD, of Western University in London, Ontario, and colleagues, noted that NHANES III data from 2009 showed that MetS prevalence is higher among people with OA than those without OA -- 59% versus 23% -- and that metabolic OA occurs in younger people ages 45 to 65.

The editorial called the OA incidence reported in the Framingham study "particularly noteworthy," as it shows that pre-existing MetS and its components are risk factors for subsequent symptomatic OA and are not just radiographic A, and the data provide circumstantial evidence for the hypothesis that one or more MetS components are causal to OA.

In addition, Appleton et al said, the Framingham data suggest that OA is a consequence of MetS rather than the reverse: "Of course, the increased risk may alternately belie the existence of common risk factors for both MetS and OA, where OA may be a later-occurring additional component of MetS. However, we feel it is most appropriate to consider metabolic OA as a complication of MetS, similar to cardiovascular disease."

The editorial emphasizes the need for carefully designed studies to determine the relative impact of increased body mass in MetS on joint loading versus metabolic derangements, including systemic inflammation: "Ruling in or out a clinically important impact of altered metabolism on incident OA risk independent of biomechanics would be a significant breakthrough in our understanding of metabolic OA and other phenotypes," Appleton et al wrote. "It would also provide a strong foundation for the development of rational treatment approaches for this pervasive and disabling disease."

Among the limitations to the study that Felson and colleagues noted were the lack of data to account for changes in MetS and its components over the 10-year follow-up period, making exposures susceptible to misclassification. And, since MetS is a disabling and sometimes fatal condition, there was a greater likelihood that participants with MetS were lost to follow-up, thereby introducing bias. Furthermore, the date of onset of symptomatic OA was not known, and the analysts could not adjust for competing risks of death.

The researchers also pointed out, as did the editorial commentators, that larger numbers of incident OA cases may have identified blood pressure as a significant OA risk factor, since the weight-adjusted analysis suggested a persistent association with blood pressure. Finally, most incident cases were knees with tibiofemoral OA, which limited the ability to examine potentially differing risks for patellofemoral and tibiofemoral OA.

The study was supported by the National Institutes of Health.

The authors and the editorial writers reported having no conflicts of interest.

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